CN104230779A - Atorvastatin calcium solvate stable crystal and preparation method thereof - Google Patents
Atorvastatin calcium solvate stable crystal and preparation method thereof Download PDFInfo
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- CN104230779A CN104230779A CN201410424921.0A CN201410424921A CN104230779A CN 104230779 A CN104230779 A CN 104230779A CN 201410424921 A CN201410424921 A CN 201410424921A CN 104230779 A CN104230779 A CN 104230779A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention relates to an atorvastatin calcium solvate stable crystal and a preparation method thereof. The mole ratio of atorvastatin calcium to 1,2-propanediol in the crystal is 1:1. The atorvastatin calcium solvate can exist in the form of absolute predominance levorotation or absolute predominance dextrorotation, or in the form of levorotation and dextrorotation in any proportion according to the solvent molecular ratio of 1:1. The atorvastatin calcium solvate stable crystal is a new crystal form; and the chemical and optical purity of the stable crystal is very high and up to 99.9%. The test proves that the appearance, related substances and content are not changed after the atorvastatin calcium solvate stable crystal is under the conditions of high temperature, strong light and high humidity for 0-30 days, which indicates that the atorvastatin calcium solvate stable crystal has favorable chemical stability and is suitable for pharmaceutical preparation manufacturing and long-term storage.
Description
Technical field
The invention belongs to biomedicine technical field, especially a kind of atorvastatin calcium solvate stable crystalline and preparation method thereof.
Background technology
Enter the second half in 20th century, under world's rapid economic development, cardiovascular disorder has been the first disease causing human death.According to World Health Organization's statistic data display: the whole world has 1,750 ten thousand people to die from cardiovascular and cerebrovascular diseases every year, has objectively driven cardiovascular drug market to increase fast.In the raising of China along with people's living standard and the change of living habit, the sickness rate of hyperlipidaemia increases year by year, the age trend rejuvenation of patient.According to statistics, normal population sickness rate is 20% ~ 40%, about there is hyperlipidaemia patient 8,000 ten thousand people in China, and every day is still with the speed increase of ten thousand people, and hyperlipidaemia is the principal element of incidence of atherosclerosis, serious cardiovascular and cerebrovascular diseases can be caused, affect the healthy of people and quality of life.
Blood fat mainly comprises cholesterol (or claiming total cholesterol TC) and triglyceride level, and exist with non-free state in circulation of blood, the macromole becoming lipoprotein such with protein binding transports.Main lipoprotein class---chylomicron, extra-low density (front-β) lipoprotein (VLDL), low density (β-) lipoprotein (LDL), with high-density (α-) lipoprotein (HDL)---these albumen are allo, and classification is normal with regard to physics-chem characteristic (density after the separation of such as electrophoretic mobility and ultracentrifugation).Lipoprotein transhipment main in blood is triglyceride level, chylomicron is maximum lipoprotein carrier, ectogenic triglyceride level through thoracic duct to Venous system, in the capillary vessel and muscle tissue of fat, the chyle triglyceride level of 90% is transported by one group of specific esterase, chylomicron is hydrolyzed into lipid acid and glycerine enters into adipocyte and muscle cell is utilized or stores, this lipase makes the endogenous triglyceride level in VLDL degrade rapidly, intermediate density lipoprotein (IDL) is caused to lose triglyceride level and apoprotein, in 2 ~ 6 hours, IDL is degraded into LDL further by being separated more triglyceride level, the transformation period of usual LDL in blood plasma is 2 ~ 3 days, VLDL is the main source of blood plasma LDL.In the internal metabolism of LDL, hepatic clearance accounts for 70%, activated acceptor site removes the most of LDL in circulation, these sites are at liver cell and the part specifically associated with LDL with the cell surface that apolipoprotein B (ApoB) combines, non-ldl receptor during then little but important with the ldl receptor binding capacity a part of LDL of LDL is recycled removed through bypass, to comprise take in by the acceptor on scavenger cell, remove, scavenger cell is movable to foam cell arterial wall become on atherosclerosis plaque.
Hyperlipidaemia be due to VLDL produce too much or removing obstacles and VLDL be transformed into LDL too much caused by.Obesity, diabetes, alcohol are excessive, nephrotic syndrome or genetic flaw can cause liver VLDL to produce too much, LDL and TC increases and be also often associated with blood high triglyceride.The removing obstacles of LDL is relevant with the textural defect of ApoB.In addition, gene or dietary factor also may cause removing obstacles, and this is mainly because ldl receptor quantity reduces or dysfunction (vigor reduction).The molecular defect of ldl receptor protein structure be ldl receptor dysfunction common genetics reason---the common mechanism of genetic flaw can in following description.In addition when the cholesterol (nubbin of chylomicron) in food arrives liver, causing intracellular cholesterol (or hepatocellular cholesterol metabolic product) to raise inhibits LDL-acceptor to synthesize, also inhibit transcribing of LDL gene, the decline of acceptor quantity causes blood plasma LDL and TC level to increase.Saturated fatty acid also makes blood plasma LDL and TC level increase, and mechanism of action is for it makes ldl receptor function reduction.Hyperlipidaemia produces too much due to VLDL or katabolism reduces and VLDL is transformed into LDL and cause LDL too much caused by.Obesity, diabetes, alcohol are excessive, nephrotic syndrome or genetic flaw can cause liver VLDL to produce too much.The removing obstacles of LDL also can cause LDL too much, and this is relevant with the textural defect of apolipoprotein B (ApoB).In addition, LDL removing obstacles also may reduce or dysfunction (vigor reduction) due to ldl receptor quantity, and this may caused by gene or dietary factor.
Atorvastatincalcuim (7-[2-(4-fluorophenyl)-3-phenyl-4-(anilino formyl radical)-5-(2-propyl group) pyrroles-1-base]-3,5-dihydroxyl enanthic acid calcium; [R, (R ﹡, R ﹡)]-2-(4-fluorophenyl)-β, alpha-dihydroxy--5-(1-methylethyl)-3-phenyl-[(anilino)-hydroxyl]-1H-pyrroles-1-Calcium salt enanthate) be a kind of selectivity HMG-CoA reductase inhibitor, it is by the anabolism of competitive inhibition histocyte inner cholesterol, feedback reconciles the activity of low-density lipoprotein ldl receptor, and then promotes that the removing of the LDL in blood plasma reduces the level of LDL in blood plasma.This drugs in idiopathic hypercholesterolemia and combined hyperlipidemia (IIa and IIb) patient, effectively can reduce the level of its total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglyceride (TG), not affect synthesis and the metabolism of high density lipoprotein cholesterol (HDL-C) simultaneously.
Atorvastatincalcuim, English name: AtorvastatinCalcium; Chemistry is by name: [R-(R, R)]-2-(4_ Gas phenyl)-β, δ-the second light industry bureau base-5-(1-methylethyl)-3-phenyl-4-[(aniline) carbonyl]-1-hydrogen-pyrroles-1-enanthic acid calcium; Molecular formula: (C
33h
34fN
20
5)
2ca; Molecular weight: 1155.34; Physico-chemical property: this product is the crystalline powder of white or off-white color; Odorless, bitter.This product is easily molten in methyl alcohol and dimethyl sulfoxide (DMSO), slightly soluble in ethanol or acetone, soluble,very slightly in water, almost insoluble or insoluble in chloroform, ether.Pharmacology type: 3-hydroxy-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor.
The mechanism of action: by suppressing HMG-CoA reductase and cholesterol to reduce plasma cholesterol and lipoprotein levels in the biosynthesizing of liver, and increase the picked-up Sum decomposition metabolism of LDL by increasing surface of hepatocytes ldl receptor number; In addition, generation and the granule number of LDL can also be reduced; Homozygote and heterozygote familial hypercholesterolemia, the blood plasma total cholesterol (Total-C) of non-familial hypercholesterolemia and combined hyperlipidemia familial patient, low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B) level can be reduced; The level of VLDL-C and TG can also be reduced, and the level of blood plasma HDL-C and aPoA-I (Apo-A1) can be improved to some extent.
Pharmacokinetics: Main Function position, at liver, is various active metabolite through Cytochrome P450 3A4 metabolism.Medicine mean plasma half-life is approximately 14 hours, but due to the impact of its active metabolite, actual is 20-30 hour to the HMG-CoA reductase inhibiting transformation period.This product protein binding rate is 98%, and major part is discharged through bile with the form of metabolite.Its result makes blood cholesterol and low-density lipoprotein cholesterol level reduce, and moderate reduces serum triglyceride level and increases blood hdl level.To atherosclerosis and coronary heart disease, there is preventive and therapeutic effect thus.
Indication: the control being used for the treatment of hypercholesterolemia and combined hyperlipidemia familial and coronary heart disease and cerebral apoplexy.Indication: primary hypercholesterolemia patient, comprise familial hypercholesterolemia (heterozygosis subtype) or combined hyperlipidemia (being equivalent to IIa and the IIb type of Fredrickson classification) patient, if dietetic treatment and other non-drug therapy curative effects are unsatisfied with, application this product can treat the rising of its total cholesterol, low density lipoprotein cholesterol (LDL-C) raises, apolipoprotein B raises and triglyceride level (TG) raises.Indication: homozygote familial hypercholesterolemia patient, atorvastatincalcuim can share or be used alone (when without other treatment means), to reduce total cholesterol and low density lipoprotein cholesterol with other Comprehensive Therapy for Correcting Lipidemia (as LDL plasma dialysis method).Usage and dosage: patient is before the treatment of beginning this product, and the low-cholesterol diet that should carry out standard controls, and also should maintain rational diet at whole treatments period.Should according to the individualized adjustment of the result for the treatment of dosage of low density lipoprotein cholesterol baseline values, therapeutic goal and patient.Conventional initial dose be 10mg once a day.The dose titration timed interval should be 4 weeks or longer.This product maximal dose be 80mg once a day.The every daily dosage portion of atorvastatincalcuim once can be taken in the intraday any time, does not affect by dining.
Atorvastatin agent is a kind of tissue selectivity HMG-CoA reductase inhibitor preparation, the biosynthesizing of energy competitive inhibition cholesterol, and cause intracellular cholesteryl to reduce, and then feedback regulation cell surface low-density lipoprotein (LDL) is by vitality of subject, promote that blood plasma LDL removes, LDL level is declined.Atorvastatincalcuim Main Function position is liver, and it is higher to the restraining effect selectivity of HMG-CoA reductase.After oral, the tl/2 of former medicine in blood plasma is about 14h, but the restraining effect of its active metabolite to HMG-CoA reductase is 20 ~ 30h, therefore its effect for reducing fat is strong and permanent, and once a day, instant, compliance is good.Meanwhile, atorvastatincalcuim due to the effect reducing triglyceride level strong, so independent medication can reach the effect reducing LDL-C and triglyceride level simultaneously.Clinical data shows, and no matter the Bloodlipid-lowering of atorvastatincalcuim and lovastatin, Pravastatin and Simvastatin are made comparisons, or compare with nicotinic acid, resene and fenofibrate, generally speaking, its effect for reducing fat is all better than said medicine.And with rosuvastain calcium ratio, atorvastatincalcuim Time To Market is long, through the clinical verification of more than ten years, thorough to its property of medicine research, can be used for diabetic, absolutely prove that it is safe and reliable.21 have been completed to the summary display of clinical study, use atorvastatincalcuim long-term treatment, adverse reactions of patients is slight, and patient medication compliance, tolerance are good.So atorvastatincalcuim is applicable to the long-term prescription of hyperlipemic patients more.Atorvastatincalcuim belongs to the first-line drug of decreasing cholesterol class, and side effect is less, is mainly used in primary hypercholesterolemia, comprises familial hypercholesterolemia (heterozygosis subtype) or combined hyperlipidemia.
Up to the present, the many atorvastatincalcuim synthesis of patent documentation and crystal formation preparation method, atorvastatincalcuim can with amorphous form or at least four kinds of known crystallized form (forms 1, form I1, form III and form IV) one of existence (US.Pat.Nos.4, 681, 893, 5, 003, 080, 5, 097, 045, 5, 103, 024, 5, 124, 482, 5, 149, 837, 5, 155, 251, 5, 216, 174, 5, 245, 047, 5, 248, 793, 5, 280, 126, 5, 397, 792 and 5, 342, 952, US.Pat.No.7, 112, 604 and US2006/0199855).
Existing research shows, the amorphous form of many medicines shows different dissolving characteristics and bioavailability pattern (KonnoT, Chem.Pharm, Bull., 1990 compared with crystallized form; 38; 2003-2007).With regard to many treatment indications of medicine, bioavailability is one of key parameter, and depends on the crystalline structure form of bulk drug used in formula of medicine.Be difficult under normal circumstances carry out amorphous substance and crystal formation crystallization preparation method respectively, the product often generated is two kinds of forms in varing proportions, amorphous and crystallization, mixture.Because the solubleness of various atorvastatin crystalline forms is different, and directly affect its bioavailability, therefore guarantee that the homogeneity of atorvastatincalcuim used in pharmaceutical preparation preparation process seems particularly important.Test proves, in under sour environment, all atorvastatincalcuims mixed in formula of medicine all can not dissolve, because the solubleness of atorvastatincalcuim is low, make to prepare the preparation (W097/3960) that biological activity is stablized, effect is consistent.
For the substance characteristics of atorvastatincalcuim instability, bibliographical information was once had to attempt to solve this difficult problem by optimizing atorvastatin pharmaceutical formulation technique.Such as, in formula prepared by tablet, add alkalescence or buffer reagent (W000/35425, W094/16603), namely according to specially apply for that the method similar approach for Pravastatin sodium described in W001/93860 strengthens the stability of atorvastatincalcuim.But in the imperfect crystal formation process that preparation is stable, in method disclosed in W001/93860, Slovenia patent application P-9900271 and W001/42209, the homogeneity that above-mentioned patent is not all described in detail about the physical parameter (being respectively crystallization and amorphous form) of atorvastatincalcuim provides the bioavailability of atorvastatincalcuim formula of medicine and bioactive relativity problem with relevant.
On the other hand, the purity of pharmaceutically active substance is considered to the important factor guaranteeing drug safety and quality always.In the synthesis production process of atorvastatincalcuim, the complicated synthesis step that multistep is different inevitably produces a large amount of structure and characteristics except target product and the similar impurity compound of atorvastatin calcium compound.In addition, because it is responsive on the impact of environment in the synthesis production process of atorvastatincalcuim, such as, oxygen in temperature, pH, humidity, light, air and carbonic acid gas and in process or storage process surrounding medium etc., these factors all likely cause atorvastatin calcium compound to be degraded, thus its biological activity is reduced, impurity compound improves.Be possible simultaneously and patient is taken to the preparation prepared future bring less desirable side effect, thus make to have a negative impact to the security of medicine.Therefore, the bulk drug active constituents of medicine as preparation requires stable and purifying to greatest extent.
Because atorvastatincalcuim is a kind of chiral non-racemic compound and as the bulk drug of preparation, therefore prepare that to remove its residual impurity in the method for high-purity raw medicine and preparation process thereof be vital.Be in chiral molecules building-up process, add expensive single chiral radicals under normal circumstances, and then take complicated sepn process to be separated by free chiral radicals.Another method is the method adopting the three-dimensional chemical transformation selected.But a kind of that above-mentioned method all needs special reaction reagent and extremely strict reaction conditions to control.
F.Toda, at Top.Curr.Chem.Vol.140, pp.43-69, utilizes the formation method of inclusion complex body to provide a kind of typical method of solvent chipal compounds in 1987.But this method rarely has for organic chemistry experimental stage at present, never in the industrialization preparation preparation of bulk drug.Trace it to its cause mainly due to the solvating solvents of reaction substrate and chirality merge after need generate stronger solvate and set up an effective separation system.Undoubtedly, for atorvastatincalcuim, this has the molecule of two chiral centres, sets up a solvation preparation method that is efficient, high yield and goes the non-targeted impurity effectively removing those steric isomers to be a problem demanding prompt solution.On the other hand, due to atorvastatincalcuim to environmental factor as light, air, environmental pH, and thermal environment is extremely responsive, and this also brings huge difficulty for the processing of its preparation and the use of patient.Therefore, atorvastatincalcuim solvation process by provide a kind of prepare simple, Atmospheric Condition under stable, bioavailability is high, be easy to effective method prepared by preparation processing.
The atorvastatincalcuim of solvation and hydrated form is produced out by the solvation of acetone (WO2006/012499), ethanol and butanols (US2005/0004206).Meanwhile, the atorvastatincalcuim of multiple hydrated form is also obtained following patent (US.Pat.No.5,969,156 in succession, US.Pat.No.5,298,627, US.Pat.No.6,992,194 and US.Pat.No.6,605.729), wherein modal is compound containing three crystal water forms.
Utilize 1,2 propylene glycol have many advantages as solvent carrier and are widely used (http://www.cfsan.fda.gov/ ~ dms/eafus.html) as wetting agent in the solvation of medicine.U.S. FDA and Bureau of Drugs Supervision of country of China ratify 1 after its security of checking, and former (auxiliary) material of 2 propylene glycol solvent prepares corresponding preparation as former (auxiliary) material of pharmaceutical preparation.As: Celecoxib (US 2006/0052432), OlanZapine (US 2006/0223794), Eplerenone (US 2005/0267302), AZithromycin (US.Pat.No.6, 977, 243, US.Pat.No.7, 105, 179), ConaZoles (US 2004/0019211), CefatriZine (JP 01290682), Cepha losporin compound (US.Pat.No.4, 091, 213, US.Pat.No.3, 970, 651, JP 105, 813/75 and CA 1, 101, 840), SGLT2 inhibitor (CN101479287B) and carvedilol phosphate salts (CN 1678305A) etc.Common example is, the solvation (WO 2004/060347) of relevant Celecoxib and OlanZapine in patent of invention illustrating in detail 1, the effect of solvation in the activity strengthening medicine of 2 propylene glycol.But, do not provide the concrete steps of more illustration and detailed solvation in this patent.
In a word, in method prepared by the atorvastatincalcuim crystal-form compound of existing research report and patent literature, the various crystal formation of acquisition or non-crystalline forms atorvastatincalcuim still total impurities is higher, optical purity is lower, and bioavailability is little.In view of the conventional crystal formation of atorvastatincalcuim to the susceptibility of the air ambient factor, bioactive unstable, formulation processing conditions harshness, the solvate stable crystalline that solvation prepares atorvastatincalcuim will be the effective ways solving this production difficult problem.
Summary of the invention
The object of the present invention is to provide a kind of atorvastatin calcium solvate stable crystalline and preparation method thereof, atorvastatincalcuim and 1 in crystallization, the ratio of 2 propylene glycol is 1:1 mol ratios, atorvastatin calcium solvate both also can exist with the dextrorotatory form of absolute predominance with the levorotatory form of absolute predominance, between or with the solvation form of the left-handed of any ratio and dextrorotation according to 1:1, mol ratio, solvent molecule ratio exist.
The object of the invention is to be achieved through the following technical solutions:
A kind of atorvastatin calcium solvate stable crystalline, structural formula is as follows:
And in described crystallization, the ratio of atorvastatincalcuim and solvent molecule is 1:1, mol ratio.
A preparation method for atorvastatin calcium solvate stable crystalline, step is as follows:
(1) atorvastatincalcuim is first dissolved in mixed solvent, concentration of ordinary dissolution is weight percentage 1 ~ 3%, and described mixed solvent is dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=1 ~ 2:100;
(2) add 1 again, 2 propylene glycol solvent, relative to atorvastatincalcuim, the add-on of 1,2 propylene glycol solvent is 0.2 ~ 0.4g/ml;
(3) adding organic cosolvent subsequently, is 0.1 ~ 0.2g/ml relative to the amount of counting of atorvastatincalcuim (g) organic cosolvent, and described organic cosolvent is one of butylacetate, Isoamyl Acetate FCC or arbitrary proportion mixture.
(4) non-shock chilling, is separated and dry acquisition sterling, obtains atorvastatincalcuim 1,2 propylene glycol solvate stable crystallines.
And described step reaction conditions is (2) 65 DEG C ~ 72 DEG C and stirs 45 ~ 60 minutes under 120rpm.
And described step reaction conditions is (3) 55 DEG C ~ 68 DEG C insulations 15 ~ 24 hours.
And the reaction conditions of described step (4) non-shock chilling is 10 DEG C ~ 15 DEG C, and static 6 ~ 10 hours.
A kind of preparation comprising atorvastatin calcium solvate stable crystalline.
And described preparation is tablet, pill, capsule and dispersion agent preparation
Advantage of the present invention and positively effect as follows:
1, the atorvastatin calcium solvate stable crystalline that the present invention obtains is a kind of new crystal formation, the stable crystalline prepared is chemical and optical purity is high, reach 99.9%, confirm through overtesting: from 0 ~ 30 day under high temperature, high light, super-humid conditions, outward appearance, material physico-chemical property, content all do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
2, the invention provides the method preparing atorvastatin calcium solvate stable crystalline, first atorvastatincalcuim is dissolved in the special solvent of the present invention by present method, i.e. dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=1 ~ 2:100, this dissolving significantly can increase the dissolution rate of atorvastatincalcuim, increase the dissolution rate of atorvastatincalcuim, can effectively increase its percent crystallization in massecuite, be follow-up 1, the solvation of 2 propylene glycol lays the foundation.
3, the invention provides best crystallization condition, add 1, after 2 propylene glycol, keep 65 DEG C ~ 72 DEG C stirrings in conjunction with 30 ~ 60 minutes or 1 hour, ensure atorvastatincalcuim and 1,2 propylene glycol fully contact, and carry out crystallization, then adopt organic cosolvent at 55 DEG C ~ 68 DEG C by atorvastatincalcuim crystalline solvate.
4, the recrystallization that the present invention obtains both had been the atorvastatincalcuim preparation raw material of 1,2 propylene glycol solvent after natural volatile dry, did not need other drying conditionss, easy and simple to handle.
5, The present invention gives best organic cosolvent is butylacetate and Isoamyl Acetate FCC, and wherein the developability of butylacetate is comparatively strong, and pungency is strong, Isoamyl Acetate FCC is delicious, after simultaneous reactions, the rate of recovery is high, the needs of more realistic production, therefore keypoint recommendation Isoamyl Acetate FCC of the present invention.Use butylacetate and Isoamyl Acetate FCC mixture time, butylacetate: the ratio of Isoamyl Acetate FCC=1:1 ~ 7 can complete crystallization, percent crystallization in massecuite and purity difference not obvious.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRD) collection of illustrative plates of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by solvent acetic acid butyl ester, embodiment 1;
Fig. 2 is differential heating scan (DSC) spectrum of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by solvent acetic acid butyl ester, embodiment 1;
Fig. 3 is atorvastatincalcuim 1,2 propylene glycol solvate crystal infrared (IR) spectrum that the present invention is prepared by solvent acetic acid isopentyl ester, embodiment 1;
Fig. 4 is the X-ray powder diffracting spectrum of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by solvent acetic acid isopentyl ester, embodiment 2;
Fig. 5 is the differential heating scan spectrum of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by solvent acetic acid isopentyl ester, embodiment 2;
Fig. 6 is atorvastatincalcuim 1, the 2 propylene glycol solvate crystal infrared spectra that the present invention is prepared by butylacetate and Isoamyl Acetate FCC arbitrary proportion mixed solvent, embodiment 2;
Fig. 7 is the X-ray powder diffracting spectrum of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by butylacetate and Isoamyl Acetate FCC arbitrary proportion mixed solvent, embodiment 3;
Fig. 8 is the differential heating scan spectrum of atorvastatincalcuim 1, the 2 propylene glycol solvate crystal that the present invention is prepared by butylacetate and Isoamyl Acetate FCC arbitrary proportion mixed solvent, embodiment 3;
Fig. 9 is atorvastatincalcuim 1, the 2 propylene glycol solvate crystal infrared spectra that the present invention is prepared by solvent acetic acid butyl ester, embodiment 3;
Figure 10 is atorvastatincalcuim 1,2 propylene glycol solvate crystal nuclear mr (NMR) hydrogen of the present invention spectrum, embodiment 1;
Figure 11 is atorvastatincalcuim 1,2 propylene glycol solvate crystal nuclear mr (NMR) carbon of the present invention spectrum, embodiment 1;
Figure 12 is atorvastatincalcuim 1,2 propylene glycol solvate crystal mass spectrum (MS) collection of illustrative plates of the present invention, embodiment 1.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention in described scope of embodiments.
The invention provides a kind of atorvastatincalcuim solvate crystal (shown in formula I), atorvastatin calcium solvate 1,2 propylene glycol, molecular formula: C
66h
68caF
2n
40
10c
3h
8o
2, molecular weight 1231.45, structural formula is as follows:
In crystallization, the ratio of atorvastatincalcuim and solvent molecule is 1:1, atorvastatin calcium solvate both also can exist with the dextrorotatory form of absolute predominance with the levorotatory form of absolute predominance, or exist with the solvent molecule ratio of the solvation form of the left-handed of any ratio and dextrorotation according to 1:1.
In the present invention, atorvastatincalcuim solvated compounds crystal adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ).See Fig. 1, Fig. 4 and Fig. 7.In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
The invention provides a kind of preparation method of atorvastatin calcium solvate, step is as follows:
(1) atorvastatincalcuim is first dissolved in mixed solvent: dimethyl sulfoxide (DMSO) (DMSO): acetone or methyl alcohol volume ratio 1 ~ 2:100, slowly dissolve in mixed solvent, concentration of ordinary dissolution is weight percentage 1 ~ 3%;
(2) add 1 again, 2 propylene glycol solvent, relative to atorvastatincalcuim (g), the add-on of 1,2 propylene glycol (ml) solvents is 0.2 ~ 0.4g/ml; Described 1,2 propylene glycol are left-handed or dextrorotation or DL;
(3) adding organic cosolvent subsequently, is 0.1 ~ 0.2g/ml relative to the amount of counting of atorvastatincalcuim (g) organic cosolvent, and organic cosolvent is butylacetate and Isoamyl Acetate FCC.
(4) be separated and dry acquisition sterling, specify that the purifying of the atorvastatincalcuim of solvation form, desolventizing and recovery method and operation.
The invention provides the preparation method of three kinds of atorvastatincalcuim solvated compounds stable crystallines, concrete operation step is as described in embodiment 1 ~ 3.
Embodiment 1
A preparation method for atorvastatincalcuim solvate crystal, step is as follows:
Various crystal formation and amorphous etc. separately or the atorvastatincalcuim of mixture be dissolved in mixed solvent with the concentration of weight percent 3% under 45 DEG C ~ 55 DEG C conditions, stir under 50 ~ 100rpm and slowly dissolve; The proportioning of mixed solvent is: dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=1:100, gets solution 50ml;
(2) add in 1,2 propylene glycol solutions of 5ml in lysate, heat 65 DEG C ~ 72 DEG C and stir 30 ~ 60 minutes under 120rpm, then filtering; Described 1,2 propylene glycol are left-handed or dextrorotation or DL;
(3) filtrate adds the butyl acetate solvent of 10ml after being cooled to 55 DEG C ~ 68 DEG C, stirs evenly, and is incubated 15 ~ 24 hours;
(4) by the mixed solution non-shock chilling to 10 of above-mentioned acquisition DEG C ~ 15 DEG C, and static 6 ~ 10 hours, crystallization, filter, obtain chemical purity up to 99.9% through natural volatile dry, maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.9%ee, stable chemical nature, is easy to the atorvastatin calcium solvate of pharmaceutical preparation processing.XRD, DSC and IR of product are see Fig. 1, Fig. 2 and Fig. 3.
Embodiment 2
A preparation method for atorvastatincalcuim solvate crystal, step is as follows:
Various crystal formation and amorphous etc. separately or the atorvastatincalcuim of mixture be dissolved in mixed solvent with the concentration of weight percent 3% under 45 DEG C ~ 55 DEG C conditions, stir under 50 ~ 100rpm and slowly dissolve; The proportioning of mixed solvent is: dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=2:100, gets solution 50ml;
(2) add in 1,2 propylene glycol solutions of the left-handed of 3ml or dextrorotation or DL in lysate, heat 65 DEG C ~ 72 DEG C and stir under 120rpm and filter for 30 ~ 60 minutes;
(3) filtrate adds the Isoamyl Acetate FCC solvent of 10ml after being cooled to 55 DEG C ~ 68 DEG C, is incubated 15 ~ 24 hours;
(4) by the mixed solution non-shock chilling to 10 of above-mentioned acquisition DEG C ~ 15 DEG C, and static 6 ~ 10 hours, crystallization, filter, obtain chemical purity up to 99.9% through natural volatile dry, maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.9%ee, stable chemical nature, is easy to the atorvastatin calcium solvate of pharmaceutical preparation processing.XRD, DSC and IR of product are see Fig. 4, Fig. 5 and Fig. 6.
Embodiment 3
A preparation method for atorvastatincalcuim solvate crystal, step is as follows:
By various crystal formation and amorphous etc. separately or the atorvastatincalcuim of mixture be dissolved in mixed solvent with the concentration of weight percent 3% under 45 DEG C ~ 55 DEG C conditions, stir under 50 ~ 100rpm and slowly dissolve; The proportioning of mixed solvent is: dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=1:100, gets solution 100ml;
(2) add in 1,2 propylene glycol solutions of the left-handed of 10ml or dextrorotation or DL in lysate, heat 65 DEG C ~ 72 DEG C and stir under 120rpm and filter for 30 ~ 60 minutes;
(3) filtrate adds the butylacetate of 25ml and the mixed solvent of Isoamyl Acetate FCC arbitrary proportion after being cooled to 55 DEG C ~ 68 DEG C, is incubated 15 ~ 24 hours;
(4) by the mixed solution non-shock chilling to 10 of above-mentioned acquisition DEG C ~ 15 DEG C, and static 6 ~ 10 hours, crystallization, filter, obtain chemical purity up to 99.9% through natural volatile dry, maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.9%ee, stable chemical nature, is easy to the atorvastatincalcuim solvate crystal of pharmaceutical preparation processing.XRD, DSC and IR of product are see Fig. 7, Fig. 8 and Fig. 9.
In above-mentioned preparation method, atorvastatincalcuim crystalline solvate good stability, can ensure the quality of pharmaceutical preparation.The chemical structure of atorvastatincalcuim used, through structure and determination of elemental analysis, has proved that chemical structure is correct.
Another object of the present invention, provides the composition comprising the atorvastatin calcium compound that atorvastatincalcuim solvate crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology, the compounds of this invention acceptable solid carrier on technology of pharmaceutics is combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particle, and can be used for the film coated tablet agent formulation for the preparation of all size and content.
Embodiment 4
Prepared by specification 10mg atorvastatincalcuim film coated tablet
Formula: atorvastatincalcuim solvation stable crystalline compound 21.32g should be taken according to 2000 film coated tablet desired raw materials and auxiliary material, calcium carbonate 50.50g, lactose 80.86g, Microcrystalline Cellulose 35.16g, carboxymethyl cellulose 11.99g, hard magnesium 1.25g.Every sheet is heavily 100mg.
Complete processing: above-mentioned material is extruded dry powder granulating after full and uniform mixing except magnesium stearate, mix and compression molding with hard magnesium after 20 eye mesh screens filter, initial nude film, after film coating, is finally prepared into every sheet heavily for 100mg ± 3.0mg atorvastatin calcium contents is 10mg film coated tablet.
Embodiment 5
Prepared by specification 20mg atorvastatincalcuim film coated tablet
Formula: atorvastatincalcuim solvation stable crystalline compound 42.64g should be taken according to 2000 film coated tablet desired raw materials and auxiliary material, calcium carbonate 101.00g, lactose 161.72g, Microcrystalline Cellulose 70.32g, carboxymethyl cellulose 23.98g, hard magnesium 2.50g.Every sheet is heavily 200mg.
Complete processing: above-mentioned material is extruded dry powder granulating after full and uniform mixing except magnesium stearate, mix and compression molding with hard magnesium after 20 eye mesh screens filter, initial nude film, after film coating, is finally prepared into every sheet heavily for 200mg ± 6.0mg atorvastatin calcium contents is 20mg film coated tablet.
Stability test: the stability of crystal formation of the present invention is studied, investigation condition is high temperature (72 DEG C ± 1 DEG C), strong illumination (4500Lx ± 500Lx), high humidity (75% and 92.5%, RH) Testing index is outward appearance, content and active substance.
Result shows: from 0 ~ 30 day under high temperature, high light, super-humid conditions, outward appearance, and related substance, content do not change, and illustrates that chemical stability is good, is applicable to manufacture and the standing storage of pharmaceutical preparation.
Under 72 DEG C and strong illumination (5000Lx) condition, the mensuration of the content of atorvastatincalcuim solvate crystal atorvastatincalcuim:
Under result shows intense light irradiation and high ambient conditions, atorvastatincalcuim solvate crystal has no degraded.
At 37 DEG C, under different relative humidity (RH) condition (75%, 92.5%), measure water content in atorvastatincalcuim solvate crystal.
Result shows: can not bound water molecule under solvate crystal natural condition.
Result shows: at 37 DEG C, and under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
The XRD diffraction analysis of atorvastatincalcuim solvate crystal: atorvastatincalcuim 1,2 propylene glycol prepared by the inventive method can pass through X-ray diffraction (XRD) and analyze, CuKa target, tube voltage 40KV, tube current 100mA.
Result shows: X-ray powder diffraction charateristic avsorption band (2 θ) value is: 4.80,5.32,7.05,7.94,9.42,10.30,12.10,13.66,14.32,16.92,17.40,19.30,19.82,21.42,22.6,23.54,24.92,26.20,26.68,27.24,28.84,30.10,31.06.Atorvastatincalcuim 1, as shown in Figure 1, interpretation of result is in table 1 for the X-ray diffractogram of 2 propylene glycol crystal.
The DSC signature analysis of atorvastatincalcuim solvate crystal: the atorvastatincalcuim 1 prepared by the inventive method, 2 propylene glycol can pass through dsc (DSC) and analyze, 50mL/min under nitrogen, heat-up rate 10 DEG C/min, temperature elevating range 50 ~ 350 DEG C, sample introduction 5mg.
Result shows a main endotherm(ic)peak at 194.4 DEG C, and peak width is 17.1 DEG C (by 184.5 ~ 201.6 DEG C).Atorvastatincalcuim 1, the DSC spectrogram of 2 propylene glycol as shown in Figure 2.
The infrared signature analysis of atorvastatincalcuim solvate crystal: atorvastatincalcuim 1,2 propylene glycol prepared by the inventive method can pass through infrared spectroscopy (2% Potassium Bromide) and analyze.Result shows its principal character absorption peak 3381, and 2970,1652,1511,1436,1315,1222,1157,844,753 and 693cm
-1place.Atorvastatincalcuim 1, the IR spectrogram of 2 propylene glycol is as Fig. 3.
Atorvastatincalcuim solvate crystal NMR analyzes: atorvastatincalcuim 1,2 propylene glycol prepared by the inventive method can pass through nuclear magnetic resonance method (NMR) and analyze, and uses deuterated dimethyl sulfoxide (DMSO-d
6) as solvent, hydrogen spectrum and carbon spectrum mensuration are carried out respectively to product.
According to Figure 10, the interpretation of result of NMR measured value (calculated value) hydrogen spectrum:
1hNMR: δ 1.000 (1.5H, d), 1.202 ~ 1.236 (1H, m), 1.359 ~ 1.492 (7H, m), 1.492 ~ 1.606 (2H, m), 1.880 ~ 1.938 (1H, m), 2.025 ~ 2.074 (1H, m), 3.151 ~ 3.248 (2H, m), 3.530 ~ 3.556 (1.5H, m), 3.717 ~ 3.765 (2H, m), 3.911 ~ 3.974 (1H, m), 4.402 ~ 4.485 (1H, m), 4.743 (1H, s), 6.246 (1H, s), 6.978 ~ 7.521 (14H, m) 9.819 (1H, s).Atorvastatincalcuim 1, the proton nmr spectra spectrogram of 2 propylene glycol as shown in Figure 10.
According to Figure 11, the interpretation of result of NMR measured value carbon spectrum:
13cNMR: δ 19.99,22.31,25.66,40.89,43.60,43.97,66.29,67.21,67.29,115.28 ~ 139.46 (17C), 160.37,162.81,166.18,178.43.Atorvastatincalcuim 1, the carbon-13 nmr spectra spectrogram of 2 propylene glycol as shown in figure 11.
Atorvastatincalcuim solvate crystal MS analyzes: atorvastatincalcuim 1,2 propylene glycol prepared by the inventive method can pass through mass spectrum (MS) and analyze.
According to Figure 12, the last molecular ion peak of MS (M+H) is 557.4, and the part that loses of its quasi-molecular ions is atorvastatincalcuim half calcium salt moieties.
Results of elemental analyses:
Measured value (calculated value): C:67.35 (67.30), H:6.21 (6.22), Ca:3.21 (3.25), F:3.11 (3.09), N:4.53 (4.55), 0:15.66 (15.59).
In sum, the present invention detects analytical results and proves that this compound chemical structure is atorvastatincalcuim 1,2 propylene glycol solvate crystal.
Table 1. atorvastatincalcuim 1,2 propylene glycol solvate stable crystalline X-ray diffraction analysis
Claims (8)
1. an atorvastatin calcium solvate stable crystalline, is characterized in that: structural formula is as follows:
2., according to atorvastatin calcium solvate stable crystalline according to claim 1, it is characterized in that: in described crystallization, the ratio of atorvastatincalcuim and solvent molecule is 1:1, mol ratio.
3. a preparation method for atorvastatin calcium solvate, is characterized in that: step is as follows:
(1) atorvastatincalcuim is first dissolved in mixed solvent, concentration of ordinary dissolution is weight percentage 1 ~ 3%, and described mixed solvent is dimethyl sulfoxide (DMSO): (acetone or methyl alcohol) volume ratio=1 ~ 2:100;
(2) add 1 again, 2 propylene glycol solvent, relative to atorvastatincalcuim, the add-on of 1,2 propylene glycol solvent is 0.2 ~ 0.4g/ml;
(3) adding organic cosolvent subsequently, is 0.1 ~ 0.2g/ml relative to the amount of counting of atorvastatincalcuim (g) organic cosolvent, and described organic cosolvent is one of butylacetate, Isoamyl Acetate FCC or arbitrary proportion mixture.
(4) non-shock chilling, is separated and dry acquisition sterling, obtains atorvastatincalcuim 1,2 propylene glycol solvate stable crystallines.
4. the preparation method of atorvastatin calcium solvate according to claim 3, is characterized in that: described step reaction conditions is (2) 65 DEG C ~ 72 DEG C and stirs 45 ~ 60 minutes under 120rpm.
5. the preparation method of atorvastatin calcium solvate according to claim 3, is characterized in that: described step reaction conditions is (3) 55 DEG C ~ 68 DEG C insulations 15 ~ 24 hours.
6. the preparation method of atorvastatin calcium solvate according to claim 3, is characterized in that: the reaction conditions of described step (4) non-shock chilling is 10 DEG C ~ 15 DEG C, and static 6 ~ 10 hours.
7. one kind comprises the preparation of atorvastatin calcium solvate stable crystalline as claimed in claim 1.
8. preparation according to claim 7, is characterized in that: described preparation is tablet, pill, capsule and dispersion agent preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945300A (en) * | 2015-06-17 | 2015-09-30 | 北京嘉林药业股份有限公司 | Purification method for I-type atorvastatin calcium |
| CN107982223A (en) * | 2017-11-27 | 2018-05-04 | 诺唯德(天津)制药有限公司 | A kind of atorvastatin agent and preparation method thereof |
| CN108675931A (en) * | 2018-05-18 | 2018-10-19 | 合肥合源药业有限公司 | A kind of low barium statin calcium and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008089557A1 (en) * | 2007-01-24 | 2008-07-31 | Apotex Pharmachem Inc. | Atorvastatin calcium propylene glycol solvates |
| CN102038682A (en) * | 2010-12-09 | 2011-05-04 | 林飞 | Pharmaceutical composition containing amlodipine and atorvastatin calcium solvate |
-
2014
- 2014-08-26 CN CN201410424921.0A patent/CN104230779A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008089557A1 (en) * | 2007-01-24 | 2008-07-31 | Apotex Pharmachem Inc. | Atorvastatin calcium propylene glycol solvates |
| CN102038682A (en) * | 2010-12-09 | 2011-05-04 | 林飞 | Pharmaceutical composition containing amlodipine and atorvastatin calcium solvate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945300A (en) * | 2015-06-17 | 2015-09-30 | 北京嘉林药业股份有限公司 | Purification method for I-type atorvastatin calcium |
| CN107982223A (en) * | 2017-11-27 | 2018-05-04 | 诺唯德(天津)制药有限公司 | A kind of atorvastatin agent and preparation method thereof |
| CN108675931A (en) * | 2018-05-18 | 2018-10-19 | 合肥合源药业有限公司 | A kind of low barium statin calcium and preparation method thereof |
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